Alveolar macrophages (AM) comprise the major cell type recovered from the lung by bronchoalveolar lavage in all species which have been studied. Immunologically-reactive lymphocytes are also normally present in the lower respiratory tract. How these cells interact to protect the lung against antigenic insult is poorly understood. Our previous studies have suggested that AM play an important role in immune regulation. Contained within the heterogeneous AM population are cells which down-regulate immunological processes in the lower respiratory tact. It is speculated that down-regulation may be attributed to interactions between specific subsets of AM and lymphocytes while other populations interact to initiated "positive" immune reactions. The present proposal is a continuation and extension of an ongoing program whose hypothesis suggests that in healthy individuals the AM functions by limiting immune reactivity, while in individuals with pulmonary disease there may be a derrangement of these normal activities. The specific aims are to provide an understanding of the functional role of AM in protecting the lung from pathological injury and to define the mechanisms by which AM mediate their immunoregulatory activities. While our goals are focused mainly on the AM, functional comparisons will be made with interstitial and pulmonary dendritic cells. The information obtained from in vitro analysis of immune function in animal models and normal human volunteers can then be compared to observations made on patients with pulmonary disease. The objectives of this proposal are directed toward evaluating the following parameters: 1) to determine why AM function ineffectively as antigen-presenting cells? Are there other types of pulmonary macrophages which function effectively? Can AM present Ag in vivo? 2) to characterize functional subpopulations of AM - Can differences be related to stage of maturation or differentiation? Do subsets express distinct surface markers detectable by monoclonal antibodies? Can we use continuous cell lines of pulmonary macrophages to study their function? 3) to described the cellular interactions and mechanisms involved in AM-mediated down-regulation -Which T- cell subsets are involved? 4) to study AM accessory and regulatory function in cell-mediated immunity -What is the role of AM in the generation of cytotoxic effector cells? 5) to compare AM from healthy and individuals with pulmonary disease for their ability to modulate immune responses. These studies should provide basic information about AM function in the normal individual and insights into changes in these functions in disease states.